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Harnessing the Blinking Heterogeneity of Fluorescent Probes: A New Take on Single-Molecule Research

利用荧光探针的闪烁异质性：单分子研究的新思路

基本信息

批准号：
2102099
负责人：
Kristin Wustholz
金额：
$ 33万
依托单位：
College of William and Mary
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2102099&HistoricalAwards=false
关键词：
Harnessing Blinking Heterogeneity Fluorescent Probes

项目摘要

In this project, funded by the Chemical Structure, Dynamics & Mechanism B Program and the Chemical Measurement and Imaging Program of the Chemistry Division, Kristin L. Wustholz of the Department of Chemistry at College of William and Mary will examine how light is emitted from molecules in order to enhance the ability to visualize structures at the nanoscale. When molecules are continuously illuminated, they respond by emitting random bursts of light, a phenomenon called blinking. This blinking behavior can be harnessed for many applications such as imaging biological structures and nanomaterials down to 10-nm length scales – a feat that is not possible with conventional optical microscopy. However, lack of understanding and control over the variations in blinking behavior from molecule to molecule across a sample fundamentally limit the image quality that can be achieved. The focus of this project is to examine and engineer blinking to produce high-quality and super-resolution images of materials that are relevant to medicine and technology. At the same time, this project provides training for undergraduate and master’s research students who learn physical, analytical, and computational techniques as well as build communication skills. Dr. Wustholz will continue her commitment to diversity and inclusion through mentoring with the Chemistry Women Mentorship Network and her use of teaching practices that benefit all students, but especially those who are low-income, first-generation, and underrepresented. This project also involves a new collaborative exchange with Temple University to further enhance scientific training and professional development of students at both institutions.The design and development of improved single-molecule probes is currently limited by several factors including: 1) unwanted heterogeneity in blinking dynamics due to contributions from multiple dark states, 2) uncontrolled environment-induced changes to blinking, and 3) reliance on spectrally-distinct dyes for multicolor imaging. The first aim of this project is to untangle the role of different dark states and their dependence on molecular structure so that blinking heterogeneity can be minimized when it is detrimental and exploited when it is useful. The initial target is a series of well-characterized xanthenes as a model system to unravel and control heterogeneity using a dark-state competition strategy. Next, the influence of molecular structure and environmental conditions will be used to control the different dark states and blinking heterogeneity of BODIPYs, promising probes whose blinking mechanisms are currently not well understood. These investigations will inform molecular design strategies for tailored emission dynamics as well as unlock new opportunities in probe design through the development of a new approach to multicolor super-resolved imaging.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在这个由化学结构、动力学与机制B项目和化学部门化学测量与成像项目资助的项目中，威廉玛丽学院化学系的Kristin L. Wustholz将研究光是如何从分子中发射出来的，以提高在纳米尺度上可视化结构的能力。当分子被持续照射时，它们会发出随机的光爆发，这种现象被称为闪烁。这种闪烁行为可以用于许多应用，例如成像生物结构和纳米材料到10纳米的长度尺度-这是传统光学显微镜无法实现的壮举。然而，缺乏对样品中分子间眨眼行为变化的理解和控制，从根本上限制了可以实现的图像质量。该项目的重点是研究和设计眨眼，以产生与医学和技术相关的材料的高质量和超分辨率图像。同时，该项目为本科生和硕士生提供物理、分析和计算技术的培训，并培养他们的沟通能力。Wustholz博士将继续致力于多样性和包容性，通过与化学女性导师网络（Chemistry Women mentor Network）进行指导，并利用有利于所有学生的教学实践，尤其是那些低收入、第一代和代表性不足的学生。该项目还包括与天普大学进行新的合作交流，以进一步加强两校学生的科学培训和专业发展。改进的单分子探针的设计和发展目前受到几个因素的限制，包括：1)由于多个暗态的贡献而导致的眨眼动力学的不均匀性，2)不受控制的环境引起的眨眼变化，以及3)依赖于光谱不同的染料进行多色成像。该项目的第一个目标是解开不同暗态的作用及其对分子结构的依赖，以便在有害时将闪烁异质性最小化，在有用时加以利用。最初的目标是一系列具有良好特征的杂蒽，作为利用暗态竞争策略揭示和控制异质性的模型系统。下一步，将利用分子结构和环境条件的影响来控制BODIPYs的不同暗态和闪烁异质性，这是一种很有前途的探针，目前闪烁机制尚不清楚。这些研究将为定制发射动力学的分子设计策略提供信息，并通过开发多色超分辨率成像的新方法，为探针设计提供新的机会。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。